Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family

Abstract

UDP-Glucuronosyltransferases (UGTs) conjugate a glucuronyl group from glucuronic acid to a wide range of lipophilic substrates to form a hydrophilic glucuronide conjugate. The glucuronide generally has decreased bioactivity and increased water solubility to facilitate excretion. Glucuronidation represents an important detoxification pathway for both endogenous waste products and xenobiotics, including drugs and harmful industrial chemicals. Two clinically significant families of UGT enzymes are present in mammals: UGT1s and UGT2s. Although the two families are distinct in gene structure, studies using recombinant enzymes have shown considerable overlap in their ability to glucuronidate many substrates, often obscuring the relative importance of the two families in the clearance of particular substrates in vivo. To address this limitation, we have generated a mouse line, termed DUgt2, in which the entire Ugt2 gene family, extending over 609 kilobase pairs, is excised. This mouse line provides a means to determine the contributions of the two UGT families in vivo. We demonstrate the utility of these animals by defining for the first time the in vivo contributions of the UGT1 and UGT2 families to glucuronidation of the environmental estrogenic agent bisphenol A (BPA). The highest activity toward this chemical is reported for human and rodent UGT2 enzymes. Surprisingly, our studies using the DUgt2 mice demonstrate that, while both UGT1 and UGT2 isoforms can conjugate BPA, clearance is largely dependent on UGT1s.

Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms

“…In support of our work, the results of a recent study (Fay et al 2015) using a novel mouse gene knockout model suggest that the Ugt1a subfamily enzymes may also be important for BPA metabolism and clearance in other (non-human) species. Specifically it was shown that complete deletion of the murine Ugt2 gene locus (including all genes encoding the Ugt2a and Ugt2b subfamily enzymes) had no effect on BPA glucuronidation activities in liver microsomes or on the rate of excretion of BPA glucuronide into bile when compared with wild-type mice.…”

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

“…In addition to recombinant enzyme systems and CYP specific inhibitors, mice lacking CYPs have been served as useful tools to estimate the contribution of CYPs to metabolism of drugs [100]. Although recently established mice lacking Ugt2 family enzymes have been used for in vivo and in vitro kinetic study of UGT substrates [101], such studies have been rarely conducted in Ugt1 -null mice. This insufficiency in the pharmacokinetic study with Ugt1 -null mice is largely attributed to the early lethality of Ugt1 -null mice [33].…”

Structure and Protein–Protein Interactions of Human UDP-Glucuronosyltransferases

“…With extensive efforts by Drs. Tukey and Koller and their colleagues, Ugt1 - and Ugt2 -knockout mice were previously developed in 2008 and 2015, respectively ( Nguyen et al, 2008 ; Fay et al, 2015 ). While Ugt2 knockout mice can be used for the phenotype analysis, Ugt1 knockout mice are lethal within 11 days after birth due to development of a bilirubin-induced irreversible brain damage, kernicterus.…”